- Matthew McConaughey as Ron Woodroof,[5] a real-life person with AIDS who smuggled unapproved pharmaceutical drugs into Texas when he found them effective at improving his symptoms. In an interview with CBS News' Lee Cowan in February 2014, McConaughey said that he selected the role because he thought it was not just a normal story, but it was a story of a "wild man".[6] McConaughey was raised near Dallas, so he was very familiar with the culture. Additionally, he thought that the script was "incredibly human, with no sentimentality". McConaughey lost nearly 50 pounds (22 kilograms) of body weight to play Woodroof in the film.[7]
- Jennifer Garner as Dr. Eve Saks, who treats people with AIDS, like Woodroof and Rayon. Upon Garner's casting, after reading the script she expressed: "I had heard about it, and I had seen pictures of Matthew losing weight. And really couldn't imagine how I was going to do it, and was so happy at home."[8]
- Jared Leto as Raymond Rayon,[9] a fictional trans woman with AIDS who helps Woodroof. To accurately portray his role, Leto lost 30 pounds (13 kilograms), shaved his eyebrows, and waxed his entire body.[10] He stated the portrayal was grounded in his meeting transgender people while researching the role.[11] He stated that when he moved to Los Angeles in 1991, he had a roommate who died of AIDS.[12] He "[worked] on Rayon's voice for weeks" and refused to break character during filming; director Vallée stated, "I don't know Leto. Jared never showed me Jared."[7]
- Denis O'Hare as Dr. Sevard[13]
- Steve Zahn as Tucker,[14] a Dallas Police Officer, Ron's friend[15]
- Michael O'Neill as Richard Barkley, an FDA agent[16] and antagonist[17]
- Dallas Roberts as David Wayne, Ron's lawyer[14]
- Griffin Dunne as Dr. Vass,[13] a Mexico-based doctor
- Kevin Rankin as T. J., Ron's friend[16]
- Bradford Cox as "Sunflower",[13] Rayon's lover, a cross-dresser dying of AIDS
- Scott Takeda as Mr. Yamata
- Adam Dunn (cameo) as a bartender
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